BACKGROUND & AIMS: OBJECT:To develop an improved short tau inversion recovery (iSTIR) technique with simultaneous suppression of fat, blood vessels and fluid to increase tumor conspicuity in the abdomen for cancer screening. MATERIALS AND METHODS:An adiabatic spectrally selective inversion pulse was used for fat suppression to overcome the reduced signal to noise ratio associated with chemically non-selective inversion pulse of STIR. A motion-sensitizing driven equilibrium was used for blood vessel suppression and a dual-echo single-shot fast spin echo acquisition was used for fluid suppression. The technique was optimized on four normal subjects and later tested on five patients referred for metastatic tumor evaluation. RESULTS:A velocity encoding of 2 cm/s achieved effective blood suppression even in small vessels. Subtraction of two images (one with 60 ms and the other with 280 ms echo time) acquired in the same echo train achieved excellent fluid suppression (>70% reduction). Simultaneous suppression of fat, blood vessels and fluid improved the tumor conspicuity compared to corresponding fat-suppressed (STIR) image. CONCLUSION:This technique generated two complementary images from a single scan: one that is equivalent to a STIR image and the other that qualitatively resembles a diffusion-weighted image and may have potential for magnetic resonance imaging cancer screening.

背景与目标：

BACKGROUND & AIMS: :To investigate the possible role of cyclin-dependent kinase 5 (cdk5) in the formation of paired helical filaments (PHFs) in muscle of patients with inclusion-body myositis (IBM), we immunolocalized cdk5, by light- and electron- microscopy, in muscle biopsies of six IBM patients. Approximately 80-90% of IBM vacuolated muscle fibers, and 10-15% of nonvacuolated fibers, contained well defined cdk5-immunoreactive inclusions that colocalized with phosphorylated tau in 70-80% of those fibers. Immunoelectronmicroscopy revealed the association of cdk5 with tau-immunoreactive PHFs. In all biopsies that contained them, regenerating muscle fibers had diffuse, moderate to strong cdk5 immunoreactivity. At all neuromuscular junctions, there was strong cdk5 immunoreactivity postsynaptically. Our study suggests that cdk5: (1) plays a role in IBM pathogenesis, possibly mediating phosphorylation of PHF-related tau; (2) is involved in muscle regeneration; and (3) has a novel function at normal neuromuscular junctions.

背景与目标： : 为了研究细胞周期蛋白依赖性激酶5 (cdk5) 在包涵体肌炎 (IBM) 患者肌肉中成对螺旋细丝 (PHFs) 形成中的可能作用，我们通过光学和电子显微镜对cdk5进行了免疫定位。6名IBM患者的肌肉活检。大约80-90% 的IBM空泡肌肉纤维和10-15% 的非空泡纤维含有明确定义的cdk5-immunoreactive夹杂物，这些夹杂物与磷酸化的tau共定位在70-80% 的这些纤维中。免疫电镜显示cdk5与tau免疫反应性PHFs相关。在包含它们的所有活检中，再生肌纤维具有弥漫性，中度至强烈的cdk5免疫反应性。在所有神经肌肉连接处，突触后都有很强的cdk5免疫反应性。我们的研究表明cdk5 :( 1) 在IBM发病机理中起作用，可能介导PHF相关tau的磷酸化; (2) 参与肌肉再生; (3) 在正常神经肌肉连接处具有新的功能。

BACKGROUND & AIMS: BACKGROUND:Tau pathology in AD spreads in a hierarchical pattern, whereby it first appears in the entorhinal cortex, then spreads to the hippocampus and later to the surrounding areas. Based on this sequential appearance, AD can be classified into six stages ("Braak stages"). The mechanisms and agents underlying the progression of Tau pathology are a matter of debate. Emerging evidence indicates that the propagation of Tau pathology may be due to the transmission of Tau protein, but the underlying pathways and Tau species are not well understood. In this study we investigated the question of Tau spreading via small extracellular vesicles called exosomes. METHODS:Exosomes from different sources were analyzed by biochemical methods and electron microscopy (EM) and cryo-EM. Microfluidic devices that allow the culture of cell populations in different compartments were used to investigate the spreading of Tau. RESULTS:We show that Tau protein is released by cultured primary neurons or by N2a cells overexpressing different Tau constructs via exosomes. Neuron-derived exosomal Tau is hypo-phosphorylated, compared with cytosolic Tau. Depolarization of neurons promotes release of Tau-containing exosomes, highlighting the importance of neuronal activity. Using microfluidic devices we show that exosomes mediate trans-neuronal transfer of Tau depending on synaptic connectivity. Tau spreading is achieved by direct transmission of exosomes between neurons. In organotypic hippocampal slices, Tau-containing exosomes in conditioned medium are taken up by neurons and microglia, not astrocytes. In N2a cells, Tau assemblies are released via exosomes. They can induce inclusions of other Tau molecules in N2a cells expressing mutant human Tau. We also studied exosomes from cerebrospinal fluid in AD and control subjects containing monomeric and oligomeric Tau. Split-luciferase complementation reveals that exosomes from CSF can promote Tau aggregation in cultured cells. CONCLUSION:Our study demonstrates that exosomes contribute to trans-synaptic Tau transmission, and thus offer new approches to control the spreading of pathology in AD and other tauopathies.

背景与目标：

BACKGROUND & AIMS: :We recently reported that Alzheimer's disease (AD) with amygdala Lewy bodies (ALB) is a distinct form of alpha-synucleinopathy that occurs in advanced AD. In AD/ALB the alpha-synuclein pathology correlated with tau pathology, but not amyloid plaques, and there was often co-localization of tau and alpha-synuclein in the same neuron. Given the anatomical connectivity of the anterior olfactory nucleus and the amygdala, which receives axonal projections from the olfactory bulb, we hypothesized that there might be a relationship between tau and alpha-synuclein pathology in the olfactory bulb and the amygdala in AD. We screened for alpha-synuclein pathology in the olfactory bulb in AD with and without ALB, and investigated its relationship with tau pathology. In 38 of 41 (93%) AD/ALB cases and 4 of 21 (19%) AD cases without ALB (AD/non-ALB), alpha-synuclein pathology was detected in the olfactory bulb. Double immunolabeling at the light and electron microscopic levels revealed co-localization of tau and alpha-synuclein in the olfactory bulb neurons and neurites. The severity of tau pathology correlated with alpha-synuclein pathology in the olfactory bulb. In addition, alpha-synuclein pathology in the olfactory bulb correlated with alpha-synuclein pathology in amygdala. Tau pathology was greater in both the olfactory bulb and amygdala in AD/ALB than in AD/non-ALB, but there was no difference in tau pathology between the two groups in other brain regions assessed. The present study shows that in AD/ALB, the olfactory bulb is nearly equally vulnerable to tau and alpha-synuclein pathology as the amygdala and suggests that neurodegeneration in these two anatomical regions is linked.

背景与目标： : 我们最近报道了患有杏仁核路易体 (ALB) 的阿尔茨海默氏病 (AD) 是发生在晚期AD中的一种独特形式的 α 突触核蛋白病。在AD/ALB中，α-突触核蛋白病理与tau病理相关，但与淀粉样斑块无关，并且tau和 α-突触核蛋白经常在同一神经元中共同定位。考虑到前嗅神经核和杏仁核的解剖连接，杏仁核从嗅球接收轴突投射，我们假设嗅球和AD杏仁核中的tau和 α-突触核蛋白病理之间可能存在关系。我们在有或没有ALB的AD嗅球中筛选了 α-突触核蛋白病理学，并研究了其与tau病理学的关系。在41例 (93% 例) AD/ALB病例中的38例和无ALB (AD/非ALB) 的21例 (19% 例) AD病例中的4例中，在嗅球中检测到 α-突触核蛋白病理。光镜和电子显微镜下的双重免疫标记显示tau和 α-突触核蛋白在嗅球神经元和神经突中的共定位。tau病理的严重程度与嗅球中的 α-突触核蛋白病理相关。此外，嗅球中的 α-突触核蛋白病理与杏仁核中的 α-突触核蛋白病理相关。AD/ALB中嗅球和杏仁核的Tau病理学均高于AD/非ALB，但在评估的其他大脑区域中，两组之间的tau病理学没有差异。本研究表明，在AD/ALB中，嗅球与杏仁核几乎同样容易受到tau和 α-突触核蛋白病理学的影响，并表明这两个解剖区域的神经变性是相关的。

BACKGROUND & AIMS: :It is unclear how tau gene mutations cause frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following intron may be pathogenic by altering E10 splicing, perturbing the normal 1:1 ratio of four versus three microtubule-binding repeat tau (4R:3R tau ratio) and forming tau inclusions. We report on a 55-year old woman with frontotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gene mutation, prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, paired helical tau filaments, increased 4R tau messenger RNA, increased 4R tau without E2 or E3 inserts, decreased 4R tau with these inserts, and a 4R:3R tau ratio greater than 1 in gray and white matter. Thus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing of E2, E3, and E10 to preferentially increase 4R tau without amino terminal inserts and promote aggregation of tau filaments into cytopathic inclusions.

背景与目标： : 目前尚不清楚tau基因突变如何导致与17号染色体 (FTDP-17) 相关的帕金森综合征的额颞叶痴呆 (FTD)，但外显子10 (E10) 或以下内含子中的突变可能通过改变E10剪接而致病，扰动四个与三个微管结合重复重复tau的正常1:1比 (4R:3R tau比) 并形成tau内含物。我们报道了一名55岁的患有额颞叶痴呆和FTDP-17家族史的女性，我们发现了新的E12 (Glu342Val) tau基因突变，突出的额颞叶神经元丢失，胞浆内tau聚集体，成对的螺旋tau细丝，增加的4R tau信使RNA，没有E2或E3插入物的4R tau增加，使用这些插入物的4R tau降低，灰色和白色物质的4R:3R tau比大于1。因此，这种新的Glu342Val突变可能通过前所未有的机制引起FTDP-17，这些机制改变E2、E3和E10的剪接，以优先增加没有氨基末端插入物的4rtau，并促进tau丝聚集到细胞病变内含物中。

BACKGROUND & AIMS: :The microtubule-associated protein tau is expressed throughout the nervous system, most highly in neurons but also in glial cells. Its functions in adult and aging mammals remain to be defined. Previous studies in mouse models found either protective or detrimental effects of genetic tau ablation. Though tau ablation prevented synaptic, network, and cognitive dysfunctions in several models of Alzheimer's disease and made mice more resistant to epileptic seizures, a recent study described a parkinsonian phenotype in aging Tau knockout mice. Here we tested cognition and motor functions in Tau(+/+), Tau(+/-), and Tau(-/-) mice at approximately 1 and 2 years of age. Tau ablation did not impair cognition and caused only minor motor deficits that were much more subtle than those associated with the aging process. Tau ablation caused a mild increase in body weight, which correlated with and might have contributed to some of the motor deficits. However, tau ablation did not cause significant dopaminergic impairments, and dopamine treatment did not improve the motor deficits, suggesting that they do not reflect extrapyramidal dysfunction.

背景与目标： : 微管相关蛋白tau在整个神经系统中表达，在神经元中表达最高，在神经胶质细胞中也表达最高。它在成年和衰老哺乳动物中的功能尚待确定。先前在小鼠模型中的研究发现了遗传tau消融的保护或有害作用。尽管tau消融在几种阿尔茨海默氏病模型中预防了突触，网络和认知功能障碍，并使小鼠对癫痫发作更具抵抗力，但最近的一项研究描述了衰老的Tau基因敲除小鼠的帕金森病表型。在这里，我们测试了大约1岁和2岁的Tau (/)，Tau (/-) 和Tau(-/-) 小鼠的认知和运动功能。Tau消融不会损害认知能力，仅引起较小的运动缺陷，比与衰老过程相关的运动缺陷要微妙得多。Tau消融导致体重轻度增加，这与某些运动缺陷相关，并可能导致某些运动缺陷。然而，tau消融并未引起明显的多巴胺能损伤，并且多巴胺治疗并未改善运动缺陷，这表明它们不能反映锥体外系功能障碍。

BACKGROUND & AIMS: :Phosphorylation of tau protein is regulated by several kinases, especially glycogen synthase kinase 3beta (GSK-3beta), cyclin-dependent protein kinase 5 (cdk5) and cAMP-dependent protein kinase (PKA). Phosphorylation of tau by PKA primes it for phosphorylation by GSK-3beta, but the site-specific modulation of GSK-3beta-catalyzed tau phosphorylation by the prephosphorylation has not been well investigated. Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. These studies reveal the nature of the inter-regulation of tau phosphorylation by the three major tau kinases.

背景与目标： : tau蛋白的磷酸化受几种激酶调节，尤其是糖原合酶激酶3β (GSK-3beta)，细胞周期蛋白依赖性蛋白激酶5 (cdk5) 和cAMP依赖性蛋白激酶 (PKA)。PKA对tau的磷酸化使其被GSK-3beta磷酸化，但是尚未很好地研究通过预磷酸化对GSK-3beta-catalyzed tau磷酸化的位点特异性调节。在这里，我们发现PKA的预磷酸化促进了Thr181，Ser199，Ser202，Thr205，Thr217，Thr231，Ser396和Ser422的GSK-3beta-catalyzed tau磷酸化，但抑制了Thr212和ser404的磷酸化。相反，预磷酸化对其随后在Thr181，Ser199，Thr205，Thr231和Ser422处被cdk5磷酸化没有显着影响; 在Ser202，Thr212，Thr217和Ser404处抑制它; 并在ser396处略微促进它。这些研究揭示了三种主要tau激酶对tau磷酸化的相互调节的性质。

BACKGROUND & AIMS: :Bisphenol A (BPA) is a well-known endocrine disruptor used to manufacture polycarbonate plastics and epoxy resins. BPA exposure especially occupational perinatal exposure to has been linked to numerous adverse effects for the offspring. Available data have shown that perinatal exposure to BPA contributes to neurodegenerative pathological changes; however, the potential mechanisms remain unclear. This study attempted to investigate the long-term consequences of perinatal exposure to BPA on the offspring mouse brain. The pregnant mice were given either a vehicle control or BPA (2, 10, 100 μg/kg/d) from day 6 of gestation until weaning (P6-PND21, foetal and neonatal exposure). At 3, 6 and 9 months of age, the neurotoxic effects in the offspring in each group were investigated. We found that the spine density but not the dendritic branches in the hippocampus were noticeably reduced at 6 and 9 months of age. Meanwhile, p-Tau, the characteristic protein for tauopathy, was dramatically increased in both the hippocampus and cortex at 3-9 months of age. Mechanically, the balance of kinase and protein phosphatase, which plays critical roles in p-Tau regulation, was disturbed. It indicated that GSK3β and CDK5, two critical kinases, were activated in most of the BPA perinatal exposure group, while protein phosphatase 2A (PP2A), one of the important phosphatases, regulated p-Tau expression through its demethylation, methylation and phosphorylation. Taken together, the present study may be translatable to the human occupational BPA exposure due to a similar exposure level. BPA perinatal exposure causes long-term adverse effects on the mouse brain and may be a risk factor for tauopathies, and the CDK5/GSK3β/PP2A axis might be a promising therapeutic target for BPA-induced neurodegenerative pathological changes.

背景与目标： : 双酚a (BPA) 是一种众所周知的内分泌干扰物，用于制造聚碳酸酯塑料和环氧树脂。BPA暴露，尤其是职业性围产期暴露，与后代的许多不良反应有关。现有数据表明，围产期暴露于BPA会导致神经退行性病理变化; 但是，潜在的机制尚不清楚。这项研究试图调查围产期暴露于BPA对后代小鼠大脑的长期影响。从妊娠的第6天至断奶 (P6-PND21，胎儿和新生儿暴露)，给予怀孕的小鼠媒介物对照或BPA (2,10，100 μ g/kg/d)。在3、6和9个月大时，研究了每组后代的神经毒性作用。我们发现，在6个月和9个月大时，海马中的脊柱密度显着降低，但树突状分支却没有显着降低。同时，在3-9个月大时，海马和皮质中的p-Tau是Tau病的特征性蛋白。从机械上讲，在p-Tau调节中起关键作用的激酶和蛋白磷酸酶的平衡受到干扰。结果表明，在大多数BPA围产期暴露组中，两种关键激酶GSK3β 和CDK5被激活，而重要的磷酸酶之一蛋白磷酸酶2A (PP2A) 通过其去甲基化，甲基化和磷酸化来调节p-Tau的表达。总而言之，由于相似的暴露水平，本研究可能可以转化为人类职业性BPA暴露。BPA围产期暴露会对小鼠大脑造成长期不良影响，并可能是taut病的危险因素，CDK5/GSK3β/PP2A轴可能是BPA诱导的神经退行性病变的有希望的治疗靶标。

BACKGROUND & AIMS: :Hyperphosphorylation and aggregation of the microtubule-binding protein tau characterize a diverse array of neurodegenerative disorders. Most of these lack mutations in the encoding MAPT gene, and the role of tau in disease pathogenesis remains controversial. Among these tauopathies is Niemann-Pick type C disease (NPC), a lysosomal storage disorder characterized by progressive neurodegeneration and premature death, most often caused by an inherited deficiency in the intracellular lipid trafficking protein NPC1. To determine the extent to which tau affects NPC pathogenesis, we generated Npc1-/- mice deficient in tau. Unexpectedly, NPC1/tau double null mutants are generated in markedly smaller litters, exhibit an enhanced systemic phenotype and die significantly earlier than NPC1 single null mutants. As autophagy is up-regulated in NPC and protein degradation through this pathway depends on movement along microtubules, we knocked down MAPT expression in NPC1-deficient human fibroblasts and examined effects on this pathway. We show that an acute reduction of tau expression in a cellular model of NPC decreases induction and flux through the autophagic pathway. Our data establish that MAPT deletion exacerbates the NPC phenotype through a mechanism independent of tau protein aggregation and identifies a critical role for tau in the regulation of autophagy in NPC1-deficient cells.

背景与目标： : 微管结合蛋白tau的过度磷酸化和聚集表征了多种神经退行性疾病。其中大多数缺乏编码MAPT基因的突变，tau在疾病发病机制中的作用仍存在争议。在这些tau病中，有尼曼-皮克C型疾病 (NPC)，这是一种溶酶体贮积障碍，其特征是进行性神经变性和过早死亡，通常是由细胞内脂质运输蛋白npc1的遗传缺陷引起的。为了确定tau对NPC发病机理的影响程度，我们生成了缺乏tau的Npc1-/-小鼠。出乎意料的是，NPC1/tau双空突变体在明显较小的凋零中生成，表现出增强的系统表型，并且比NPC1单个空突变体明显更早死亡。由于自噬在NPC中被上调，并且通过该途径的蛋白质降解取决于沿微管的运动，因此我们下调了NPC1-deficient人成纤维细胞中的MAPT表达，并检查了对该途径的影响。我们显示，NPC细胞模型中tau表达的急剧降低会降低自噬途径的诱导和通量。我们的数据表明，MAPT缺失通过独立于tau蛋白聚集的机制加剧了NPC表型，并确定了tau在NPC1-deficient细胞自噬调节中的关键作用。

BACKGROUND & AIMS: :The microtubule-associated protein tau is important to normal neuronal function in the mammalian nervous system. Aggregated tau is the major component of neurofibrillary tangles (NFTs), present in several neurodegenerative diseases, including Alzheimer's and frontotemporal dementia with Parkinsonism (FTDP). Splicing misregulation of adult-specific exon 10 results in expression of abnormal ratios of tau isoforms, leading to FTDP. Positions +3 to +16 of the intron downstream of exon 10 define a clustering region for point mutations that are found in FTDP. The serine/arginine-rich (SR) factor 9G8 strongly inhibits inclusion of tau exon 10. In this study, we established that 9G8 binds directly to this clustering region, requires a wild-type residue at position +14 to inhibit exon inclusion, and RNAi constructs against 9G8 increase exon 10 inclusion. These results indicate that 9G8 plays a key role in regulation of exon 10 splicing and imply a pathogenic role in neurodegenerative diseases.

背景与目标： : 微管相关蛋白tau对哺乳动物神经系统的正常神经元功能很重要。聚集的tau是神经原纤维缠结 (nft) 的主要成分，存在于几种神经退行性疾病中，包括阿尔茨海默氏病和患有帕金森病 (FTDP) 的额颞叶痴呆。成人特异性外显子10的剪接失调导致tau亚型异常比例的表达，导致FTDP。外显子10下游的内含子的位置3至16定义了在FTDP中发现的点突变的聚类区域。富含丝氨酸/精氨酸 (SR) 因子9G8强烈抑制tau外显子10的包含。在这项研究中，我们确定9G8直接与该聚类区域结合，需要在14位的野生型残基来抑制外显子包含，并且针对9G8的RNAi构建体增加了外显子10的包含。这些结果表明，9G8在调节外显子10剪接中起关键作用，并暗示了在神经退行性疾病中的致病作用。

BACKGROUND & AIMS: :The appearance of neurofibrillary tangles (NFT), one of the major hallmarks of Alzheimer's disease (AD), is most likely caused by inappropriate phosphorylation and/or dephosphorylation of tau, eventually leading to the accumulation of NFTs. Enhanced phosphorylation of tau on Ser(262) is detected early in the course of the disease and may have a role in the formation of tangles. Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). Furthermore, we observed elevated interactions between MARK2 and tau in post-mortem human AD brains, compared to samples from non-demented elderly controls. Our results from transfected cells demonstrate a specific interaction between MARK2 and tau, as well as MARK2-dependent phosphorylation of tau at Ser(262). Furthermore, the elevated interactions between MARK2 and tau in AD brain sections suggests that MARK2 may play an important role in early phosphorylation of tau in AD, possibly qualifying as a therapeutic target for intervention to prevent disease progression.

背景与目标： : 神经原纤维缠结 (NFT) 的出现是阿尔茨海默氏病 (AD) 的主要标志之一，很可能是由tau的不适当磷酸化和/或去磷酸化引起的，最终导致NFT的积累。在疾病过程的早期检测到Ser(262) 上tau的增强磷酸化，并且可能在缠结的形成中起作用。已知几种激酶如微管亲和调节激酶 (MARK) 、蛋白激酶A、钙钙调蛋白激酶II和检查点激酶2在体外使Ser(262) 上的tau磷酸化。在这项研究中，我们利用原位邻近连接测定法来研究MARK2 (四种标记同工型之一) 在AD中的作用。我们证明，在稳定转染的表达人重组tau的NIH/3T3细胞中，MARK2与tau相互作用并在Ser(262) 磷酸化tau。星形孢菌素，一种蛋白激酶抑制剂，显著降低了MARK2和tau之间的相互作用，也降低了Ser(262) 处tau的磷酸化。此外，与来自非痴呆的老年对照的样本相比，我们观察到死后人类AD大脑中MARK2和tau之间的相互作用升高。我们来自转染细胞的结果证明了MARK2和tau之间的特异性相互作用，以及在Ser(262) 处tau的MARK2-dependent磷酸化。此外，在AD脑切片中MARK2和tau之间的相互作用升高表明，MARK2可能在AD中tau的早期磷酸化中起重要作用，可能有资格作为干预预防疾病进展的治疗靶标。

BACKGROUND & AIMS: :The microtubule-associated tau protein has long been considered an axon-specific protein. Although many articles describe the subcellular localization of tau as regulated by post-modification in cultured cells, the intracellular regulation of its distribution in living animals has yet to be elucidated. In the present study, we demonstrate that phosphorylation alters tau polarity in Drosophila melanogaster. Interestingly, it was observed that expression of phosphorylation-incompetent tau impaired neurite growth more severely than either hyperphosphorylated or pseudophosphorylated tau. We also found that inducible expression of hyper- or pseudo-phosphorylated tau in adult flies strikingly prolonged their lifespan. This study offers an alternative tauopathic model by demonstrating that hyperphosphorylated tau has a beneficial effect on the nervous system. This is also corroborated by common effects seen in a variety of organisms in response to various stresses. We hope that this important animal model leads to a paradigm shift in thinking about hyperphosphorylated tau, which plays a protective role in nervous systems rather than the toxic role that many have historically been given to it.

背景与目标： : 微管相关的tau蛋白长期以来一直被认为是轴突特异性蛋白。尽管许多文章描述了tau的亚细胞定位是由培养细胞中的后修饰调节的，但其在活体动物中的分布的细胞内调节尚未阐明。在本研究中，我们证明了磷酸化改变了果蝇的tau极性。有趣的是，观察到磷酸化无能的tau的表达比过度磷酸化或伪磷酸化的tau更严重地损害了神经突的生长。我们还发现，成年果蝇中超或假磷酸化tau的诱导型表达显着延长了其寿命。这项研究通过证明过度磷酸化的tau对神经系统具有有益的作用，提供了另一种tauopathic模型。在各种生物中响应各种压力的常见影响也证实了这一点。我们希望这种重要的动物模型会导致对过度磷酸化tau的思考发生范式转变，tau在神经系统中起着保护作用，而不是历史上许多人对它的毒性作用。

BACKGROUND & AIMS: :It has not been well explored how NPs may induce some adverse effects on the biological systems. In this research, the interaction of cobalt oxide NPs (Co3O4 NPs) with tau protein and PC-12 cell line, as nervous system models, was investigated with several approaches including fluorescence spectroscopy, CD spectroscopy, docking study, MTT, LDH, AO/EB dual staining, and flow cytometry assays. Fluorescence investigation displayed that Co3O4 NPs spontaneously mediate the formation of a static complex with tau protein through hydrogen bonds and van der Waals forces. Docking study also revealed that Ser and Gln residues play important roles in the formation of hydrogen bonds between tau and Co3O4 NPs. Far UV-CD measurement determined that Co3O4 NPs changed the unfolded structure of tau protein toward a more folded conformation. Moreover, Co3O4 NPs demonstrated to stimulate the reduction of PC-12 cell viability through membrane leakage, fragmentation of DNA, apoptosis, and necrosis. In conclusion, Co3O4 NPs may trigger marked alterations on the tertiary and secondary structure of tau protein. Also, the dose of Co3O4 NPs is the crucial factor which induces their adverse effects on the cells. Because, all side effects of NPs are not well explored, additional detailed experiments are more needed.

背景与目标： : 尚未很好地探讨NPs如何对生物系统产生某些不利影响。在这项研究中，氧化钴NPs (Co3O4 NPs) 与tau蛋白和PC-12细胞系 (作为神经系统模型) 的相互作用通过多种方法进行了研究，包括荧光光谱，CD光谱，对接研究，MTT，LDH，AO/EB双重染色和流式细胞仪检测。荧光研究表明，Co3O4 np通过氢键和范德华力自发介导与tau蛋白形成静态复合物。对接研究还表明，Ser和Gln残基在tau和Co3O4 np之间的氢键形成中起重要作用。Far uv-cd测量确定Co3O4 np将tau蛋白的未折叠结构改变为更折叠的构象。此外，Co3O4 np通过膜渗漏、DNA断裂、凋亡和坏死刺激PC-12细胞活力的降低。总之，Co3O4 np可能会触发tau蛋白的三级和二级结构发生明显变化。此外，Co3O4 NPs的剂量是诱导其对细胞产生不利影响的关键因素。由于NPs的所有副作用都没有得到很好的探索，因此更需要进行更详细的实验。

BACKGROUND & AIMS: :Abnormal protein aggregation is a common characteristic of many neurodegenerative diseases of the brain. Filamentous deposits made of the microtubule-associated protein tau constitute a major defining characteristic of several neurodegenerative diseases known as tauopathies. The role of tau in neurodegeneration has been clarified by the identification of genetic mutations in the tau gene in cases with familial frontotemporal dementia and parkinsonism linked to chromosome 17. Furthermore, some sporadic tauopathies are associated with tau gene polymorphisms. Although it is still debated how tau gene mutations lead to neuronal death, it is clear that different mutations lead to tau pathologies with characteristics similar to those found in sporadic tauopathies. These findings have definitely shown that in tauopathies tau aggregation is directly associated with development of neurodegeneration and neuronal death.

背景与目标： : 蛋白质聚集异常是许多大脑神经退行性疾病的共同特征。由微管相关蛋白tau制成的丝状沉积物构成了几种神经退行性疾病 (称为tau病) 的主要特征。通过鉴定与17号染色体相关的家族性额颞叶痴呆和帕金森病的tau基因的遗传突变，可以阐明tau在神经变性中的作用。此外，一些零星的tau病与tau基因多态性有关。尽管仍在争论tau基因突变如何导致神经元死亡，但很明显，不同的突变会导致tau病变，其特征与散发性tau病变相似。这些发现已经明确表明，在tauopathies中，tau聚集与神经变性和神经元死亡的发展直接相关。

BACKGROUND & AIMS: JNK and p38, two members of the MAP kinase family, are strongly induced by various stresses including oxidative stress and have been involved in regulation of apoptosis. As both kinases phosphorylate tau protein in vitro, we have investigated their immunohistochemical localization in a group of neurodegenerative diseases characterized by intracellular deposits of hyperphosphorylated tau. Cases included Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Gerstmann-Sträussler-Scheinker disease-Indiana kindred, and frontotemporal dementia with parkinsonism linked to chromosome 17. In all tissue samples, strong immunoreactivity for both MAP kinases was found in the same neuronal or glial cells that contained tau-positive deposits. By double immunohistochemistry, JNK and p38 colocalized with tau in the inclusions. Analysis of apoptosis-related changes (DNA fragmentation, activated caspase-3) showed that the expression of JNK and p38 was unrelated to activation of an apoptotic cascade. Our data indicate that phospho-JNK and phospho-p38 are associated with hyperphosphorylated tau in a variety of abnormal tau inclusions, suggesting that these kinases may play a role in the development of degenerative diseases with tau pathology.

背景与目标： MAP激酶家族的两个成员JNK和p38受到包括氧化应激在内的各种压力的强烈诱导，并参与了细胞凋亡的调节。由于两种激酶都在体外磷酸化tau蛋白，因此我们研究了它们在一组神经退行性疾病中的免疫组织化学定位，这些神经退行性疾病的特征是过度磷酸化tau的细胞内沉积。病例包括阿尔茨海默氏病，Pick病，进行性核上性麻痹，皮质基底变性，Gerstmann-strä ussler-Scheinker病-Indiana kindred和与17号染色体相关的帕金森氏症的额颞叶痴呆。在所有组织样品中，在含有tau阳性沉积物的同一神经元或神经胶质细胞中发现了两种MAP激酶的强免疫反应性。通过双重免疫组织化学，JNK和p38与tau共定位在包裹体中。对凋亡相关变化 (DNA片段化，激活的caspase-3) 的分析表明，JNK和p38的表达与凋亡级联的激活无关。我们的数据表明，磷酸-JNK和phospho-p38与多种异常tau内含物中的过度磷酸化tau有关，这表明这些激酶可能在tau病理退行性疾病的发展中起作用。